Cardiovascular Research Foundation

Columbia University Medical Center

New York City, NY

Functionally Insignificant,

Vulnerable Plaque: Do You Want

to Treat? - YES! I DO! -

Akiko Maehara, MD

Affiliation/Financial Relationship Company

Grant/ Research Support: Boston Scientific Corp.

Consultant: Boston Scientific Corp.

Speaker Fee: St Jude Medical, Volcano Corporation

Disclosure Statement of Financial InterestWithin the past 12 months, I or my spouse/partner have

had a financial Interest /arrangement or affiliation with

the organization(s) listed below

MLA=4.0mm2, TCFA

*Septal

*

*

9 Months later

Index

prox

A PROSPECT Case

700 pts with ACSUA (with ECGΔ) or NSTEMI or STEMI >24º

undergoing PCI of 1 or 2 major coronary arteries

at up to 40 sites in the U.S. and Europe

PCI of culprit lesion(s)

Successful and uncomplicated

Formally enrolled

Metabolic S.

• Waist circum

• Fast lipids

• Fast glu

• HgbA1C

• Fast insulin

• Creatinine

Biomarkers

• Hs CRP

• IL-6

• sCD40L

• MPO

• TNFα

• MMP9

• Lp-PLA2

• others

PI: Gregg W. Stone

Sponsor: Abbott Vascular; Partner: Volcano

The PROSPECT Trial

Thick-cap FA Thin-cap FA PIT FibrocalcificFibrous

VH-IVUS Classification

More than 10%

Confluent

Necrotic CoreNO more than 10%

Confluent Necrotic

Core

More than 10%

confluent

calcium

More than 15%

Fibrofatty

PROSPECT: MACEM

AC

E (

%)

Time in Years0 1 2 3

All

Culprit lesion (CL) related

Non culprit lesion (NCL) related

Indeterminate

0

5

10

15

20

25

Number at risk

20.4%

12.9%

11.6%

2.7%

13.2%

7.9%

6.4%

0.9%

18.1%

11.4%

9.4%

1.9%

ALL 697 557 506 480

CL related 697 590 543 518

NCL related 697 595 553 521

Indeterminate 697 634 604 583

PROSPECT: MACE

3-year follow-up, non hierarchical

AllCulprit

lesion related

Non culprit

lesion related

Indeter-

minate

Cardiac death 1.9% (12) 0.2% (1) 0% (0) 1.8% (11)

Cardiac arrest 0.5% (3) 0.3% (2) 0% (0) 0.2% (1)

MI (STEMI or NSTEMI) 3.3% (21) 2.0% (13) 1.0% (6) 0.3% (2)

Unstable angina 8.0% (51) 4.5% (29) 3.3% (21) 0.5% (3)

Increasing angina 14.5% (93) 9.2% (59) 8.5% (54) 0.3% (2)

Composite MACE 20.4% (132) 12.9% (83) 11.6% (74) 2.7% (17)

Cardiac death, arrest or MI 4.9% (31) 2.2% (14) 1.0% (6) 1.9% (12)

Rates are 3-yr Kaplan-Meier estimates (n of events)

PROSPECT: Multivariable Correlates

of Non Culprit Lesion Related Events

Independent predictors of lesion level events by Cox

Proportional Hazards regression

Variables entered into the model: minimal luminal area (MLA) ≤4.0 mm2; plaque burden at the MLA (PBMLA)

≥70%; external elastic membrane at the MLA (EEMMLA) <median (14.1 mm2); lesion length ≥median (11.2

mm); distance from ostium to MLA ≥median (30.4 mm); remodeling index ≥median (0.94); VH-TCFA.

Variable HR [95% CI] P value

PBMLA ≥70% 5.03 [2.51, 10.11] <0.0001

VH-TCFA 3.35 [1.77, 6.36] 0.0002

MLA ≤4.0 mm2 3.21 [1.61, 6.42] 0.001

Remodeling Index to predict MACE

Inaba S, et al, JACC Img in press

Relationship between remodeling index and MLA

Inaba S, et al, JACC Img in press

Remodeling Index and MACE

Inaba S, et al, JACC Img in press

VIVA Study (VH-IVUS in Vulnerable Atherosclerosis)

Calvert PA et al. JACC Img 2011;4:894–901

167 pts with stable CAD or ACS underwent 3-vessel VH-IVUS imaging;

1,096 plaques were classified; median follow-up 625 days

18 MACE (death [2], MI [2] or revasc [14]) occurred in 16 pts from

19 lesions (13 nonculprit lesions and 6 culprit lesions)

Univariate predictors of non-culprit MACE

Grayscale IVUS characteristics VH-IVUS lesion classification

MLA <4mm2

Plaque Burden

>70%

Remodeling

Index

Plaque

Volume

p=0.13

p=0.01

p=0.03

p=0.47

p=0.46

p=0.59

p=0.83

p=0.71

p=0.37

p=0.64

p=0.04

0.1

Hazard Ratio (95% CI)

1 10 1000.01 0.1

Hazard Ratio (95% CI)

1 10 1000.01

PIT

Off scale HR = 2686

[1.94-3.72 x 106]

Fibrocalcific

Non-calcified ThCFA

Calcified ThCFA

Non-calcified TCFA

Calcified TCFA

Total TCFA

ATHEROREMO-IVUS Study

Cheng JM et al. Eur Heart J 2013, doi:10.1093/eurheartj/eht484

• 581 patients in 2008-2011

• 1 year follow-up

• MACE (non-culprit related

ACS, unplanned coronary

revascularization or

indeterminate mortality)

• Single center, prospective

OCT Predictor for Progression

• DESIGN: Prospective, Single

Center, Observational Study

• OBJECTIVE: To evaluate OCT

predictor for disease

progression in non-culprit

lesions

• METHODS:

1. 3 vessel OCT after successful

PCI of culprit lesions

2. 6-9 month follow-up

3. Progression: Late loss>0.4mm

69 Non-culprit lesion in 69 vessels in 53 pts

• 56 non-culprit

lesion in 40 pts

• 3 ACS events in 3pts

• 10 progression without

event in 10 pts

Baseline Follow-up

Uemura et al, Eur Heart J 2011 doi:1093/eurheart/ehr284

OCT Predictors for Progression

of Non-Culprit Lesions

Micro

Channel

TCFA

Thrombus

Laceration

Macrophage

20 (4.9-82.6) 20 (4.8-82.6) 12 (2.2-64.3) 10.2 (2.8-37.8) 9.6 (2.6-35.6)

Odds

Ratio

Incid

en

ce (

%)

Uemura et al, Eur Heart J 2011 doi:1093/eurheart/ehr284

Is there a characteristic signal of

lesions that cause STEMI?Near infrared spectroscopy (InfraReDx) was performed immediately

after infarct artery recanalization in 20 pts with STEMI

The NIRS

chemograms of all 20

STEMI pts. The culprit

segments contain LCP

in 19 cases (95%), all

with large plaque

burden.

Madder RD. JACC Interv 2013

Is there a characteristic signal of

lesions that cause STEMI?Near infrared spectroscopy (InfraReDx) was performed immediately

after infarct artery recanalization in 20 pts with STEMI

Madder RD. JACC Interv 2013

Ability of NIRS (maxLCBI4mm)

and IVUS (plaque burden and

calcification) to distinguish the

culprit segment from non-

culprit segments of the

STEMI culprit vessel:

AUC for maxLCBI4mm = 0.90

AUC for plaque burden = 0.86

1.0

0.8

0.6

0.4

0.2

0.0

0.0 0.2 0.4 0.6 0.8 1.0

MaxLCBI4mm c=0.90

PB, c=0.86

1 - Specificity

Sensitiv

ity

FAME: Primary Endpoint

Tonino PAL et al. NEJM 2009;360:213–24

FFR-guided

(n=509)

30 days

2.9% 90 days

3.8%180 days

4.9% 360 days

5.3%

Angio-guided

(n=496)

Absolute difference in MACE-free survival

Days

Fre

ed

om

fro

m d

ea

th, M

I, r

eva

sc

0 60 120 180 240 300 360

0.70

0.75

0.80

0.85

0.90

0.95

1.00

MACE 13.3% vs. 18.2%

P=0.02

1005 pts with MVD (83% CSA) undergoing PCI with DES

were randomized to FFR-guided vs. angio-guided intervention

Lesions with angio

DS>50%, but FFR>0.8

FAME Trial: Stent Use

RCTs of EES vs. Other DES (n-16,383):

1-year definite stent thrombosis

p=0.01

p<0.001

p<0.001

4 RCTs

6,789 pts

5 RCTs

7,302 pts

1 RCTs

2,292 pts

FAME: With better stents????

Tonino PAL et al. NEJM 2009;360:213–24

FFR-guided

(n=509)

30 days

2.9% 90 days

3.8% 180 days

4.9%360 days

5.3%

Absolute difference in MACE-free survival

Days

Fre

ed

om

fro

m d

ea

th, M

I, r

eva

sc

0 60 120 180 240 300 360

0.70

0.75

0.80

0.85

0.90

0.95

1.00

Angio-guided

(n=496)

1005 pts with MVD (83% CSA) undergoing PCI with DES

were randomized to FFR-guided vs. angio-guided intervention

NO longer significant

difference

Treatment of lesions with

DS>50%, FFR>0.8 will not

make difference.

PROSPECT II Study

PROSPECT ABSORB RCT

900 pts with ACS after successful PCI

3 vessel IVUS + NIRS (blinded)

≥1 IVUS lesion with ≥70% plaque burden present?

Routine angio/3V IVUS-NIRS FU at 2 years

Yes(N=300)

No(n=600)

ABSORB BVS

+ GDMT (N~200)

GDMT(N=100)

R

2:1

Clinical FU for ≥3 years

Impact of plaque burden

McPherson JA et al. JACC Img 2012;5:S76–85

Me

dia

n 3

.4 y

r M

AC

E r

ate

pe

r le

sio

n (

%)

0.0%0.6% 0.5%

2.5%

9.5%

0%

2%

4%

6%

8%

10%

12%

<40% 40% - 50% (n=904)

50% - 60% (n=1,239)

60% - 70% (n=798)

≥70% (n=298)

Plaque burden

thousands

PROSPECT: Correlates of Non-Culprit

Lesion Related Events

PROSPECT II Study

PROSPECT ABSORB RCT

- Primary endpoints and analysis -

PROSPECT II

Endpoints: Composite MACE (cardiac death, cardiac

arrest, MI, or unstable or progressive angina requiring

rehosp or revasc) adjudicated to non-culprit lesions

Analysis: Multivariable predictors, including clinical, QCA,

IVUS and NIRS (patient and lesion level)

PROSPECT ABSORB

Endpoints and analysis: IVUS MLA at 2 years (superiority,

powered); Death, TV-MI, TLR (noninferiority, not powered)

LMCA Defer by FFR

Hamilos, Circ, 120:1505, Lindstaedt, Am H J, 2006;152;156, Jasti ,Circ, 2004;110:2831, Bech, Heart, 2001;86:547

% M

AC

E F

ree

Defer Revasc Defer Revasc Defer Revasc Defer Revasc

9

47

1

43 0 2

1

136

73

24

27

41

14

24

30

Any Death

LMCA revasc

Other revasc

FFR=0.8Lindstaedt, 2006 Jasti, 2004 Bech, 2001

(%)

Hamilos, 2009

FFR=0.75

Defer: 5-year

survival 89.8%

DS 50-59% DS 60-69%

DS 70-79% DS 80%

Chaitman et al, AJC 1981;48: 765-777

Medical:309/CABG:1183

Natural History of Left Main Disease

YES!

Summary

• Does morphology predict future event?

• Does physiology predict future event?

• Is only physiology enough?

• Should we treat vulnerable plaque in

physiologically non-significant lesion?

YES!

We will answer in PROSPECT2!

I believe NO…